Ofatumumab monotherapy in relapsed/refractory mantle cell lymphoma - a phase II trial

Mantle cell lymphoma (MCL), an uncommon subtype of non-Hodgkin lymphoma (NHL), is considered one of the more aggressive lymphoid tumours. Despite the use of novel treatment regimens, MCL remains incurable and the focus of therapy is on the depth and duration of remission. The chimeric CD20 monoclonal antibody rituximab is a commonly used therapy in lymphoma and rituximab monotherapy shows some efficacy in MCL (Foran et al, 2000). It has recently been shown to improve the overall survival in MCL when added to combination chemotherapy, without increasing treatment toxicity (Rule et al, 2011). Ofatumumab is a fully human type 1 CD20 monoclonal antibody that targets a novel epitope on the CD20 molecule (Teeling et al, 2006). This allows closer binding to the cell surface, which is thought to contribute to both its increased ability to activate complement-dependent cytotoxicity (CDC) and the longer off-rate compared to rituximab. Ofatumumab has shown single agent activity in the treatment of chronic lymphocytic leukaemia (CLL) (Coiffier et al, 2008) and relapsed/refractory follicular lymphoma (Hagenbeek et al, 2008) with overall response rates of 44% and 42%, respectively. No dose-limiting toxicities occurred in either trial and efficacy was seen at all doses administered. Ofatumumab has now been approved by both the American and European licensing authorities for the treatment of refractory CLL and trials of ofatumumab in the treatment of NHL subtypes are ongoing. Here we report an open-label phase II single-arm study of ofatumumab monotherapy for relapsed/refractory MCL conducted in three centres in the UK (see Appendix S1 for details). 12 patients were enrolled (of a planned 34 – the trial was halted at the first predetermined evaluation point as insufficient response had been obtained). The treatment schema was an initial infusion of ofatumumab 300 mg, followed by 4 weekly treatments of 1 g. Of the 12 patients enrolled in the trial, 11 were male and one female. The median age of the patients was 64 years (range 54–69). Median stage of disease was 4 (range 2–4) and median Eastern Cooperative Oncology Group (ECOG) performance status was 0 (range 0–1). Bone marrow involvement was present in six patients (50%), three of whom (25%) had bulky disease (defined as ≥1 lymph node measuring ≥10 cm). The median number of prior lines of therapy was 3 (range 1–7) and three patients (25%) had previously received rituximab. One patient had relapsed following an autograft. The median white cell count was 7·45 × 109/l (range 2·4–308·5 × 109). Ten of the twelve patients (83%) received all five doses of ofatumumab. For the 12 enrolled patients there was an overall response rate of 8·3% with a median overall survival of 11·2 months (range 3·5–30·6 months). Only one of the 12 patients achieved a partial remission and six patients (50%) achieved stable disease. The five remaining patients had progressive disease (Fig 1). While this response rate is low, it was clear to the investigators that more patients demonstrated clinical responses after administration of the 4th or 5th infusion. However these responses were not durable and were not objectively recorded radiologically as a consequence of the timing of the first response assessment (30 d following the last dose of ofatumumab). As the majority of the patients had stable/progressive disease by their first response assessment, it was not possible to calculate progression-free survival. In line with other studies of ofatumumab, the drug was well tolerated in our study, with the most striking side effect being fatigue – 22 episodes in nine patients (75% patients affected). This was pronounced but short lived, occurring after infusions and generally resolving completely within 2 d. Although significant levels of fatigue were noted during other trials, the prevalence of this symptom in the MCL patients was much higher than noted with other diseases [75% MCL vs. 15% diffuse large B cell lymphoma (DLBCL) (Coiffier et al, 2010) and 14% in follicular lymphoma (Czuczman et al, 2012)]. Further details of toxicities can be found in Table 1. The dosing schedule used in this trial was based on a previous study of ofatumumab in NHL (Hagenbeek et al, 2008). This differs from the CLL regimen, which adopts eight doses of ofatumumab (Coiffier et al, 2008) instead of the five given in this trial. Ofatumumab is clearly efficacious in CLL but is used at much higher doses than in NHL (300 mg dose 1 and then 2000 mg given weekly for 7 weeks) to take account of the low CD20 expression. An extended treatment regimen, as used in CLL, may have led to an improvement in the observed responses. This contention is backed up by the findings that the pharmacokinetics of ofatumumab are non-linear (Hagenbeek et al, 2008). During their dose requirement estimation experiments Bleeker et al (2007) found tumour volume to significantly impact on the pharmacokinetics of ofatumumab. It is notable that the one patient who responded well to ofatumumab in this study with a good partial remission had a significantly lower tumour volume than the majority of the other patients enrolled [sum of the product of the diameters (SPD) 2306 vs. median SPD 6606]. The response rate seen in this trial was lower than those seen with both single agent rituximab [overall response rate (ORR) 33–38%] (Foran et al, 2000) and single agent obinutuzumab (GA101; best overall response 27%)(Morschhauser et al, 2013) in MCL. It is broadly similar to the response seen with ofatumumab monotherapy for heavily pre-treated DLBCL patients (ORR 11%) (Coiffier et al, 2010) compared with a 58% response rate in CLL (Wierda et al, 2010). Whether it will have a place in NHL treatment remains to be seen and, as with rituximab, synergy with chemotherapeutic agents seems likely. Trials of ofatumumab in combination with chemotherapeutic regimens for NHL are ongoing. In a difficult-to-treat cohort of relapsed/refractory MCL patients we may find that combinations of the newer CD20 monoclonal antibodies (ofatumumab and obinutuzumab) with lenalidomide or novel therapies, such as mammalian target of rapamycin (mTOR) inhibitors or Bruton tyrosine kinase inhibitors, may be effective once the dosing of these antibodies is optimized. Based on our experience, an enhanced exposure to ofatumumab, adopting a more intensive/prolonged dosing schedule, may be more effective in MCL and should be considered for subsequent studies. MF performed the research, analysed the data and wrote the manuscript, MD performed the research and critically reviewed the manuscript, RJ performed the research and critically reviewed the manuscript, MB acquired the data and critically reviewed the manuscript, SR designed the trial, performed the research and critically reviewed the manuscript. Mrs Sheila Bullard managed the trial administration and maintained the trial database Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.